Novel FLCN mutations in Chinese patients

The gene FLCN is inactivated in individuals with BHD syndrome. The FLCNgene encodes the protein Folliculin, which is a putative tumour suppressor. Over 150 different FLCN mutations have been identified, most of which are likely to be pathogenic (LOVD-hosted FLCN mutation database). The majority of these mutations are frameshift, nonsense, insertion/deletion, or splice site mutations, resulting in truncation and inactivation of the encoded protein folliculin. FLCN consists of 14 exons spanning approximately 20 kb of genomic DNA (Nickerson et al., 2002).

Novel FLCN mutations are still being identified and here we discuss two case studies with novel mutations found in patients in China:

Li et al. (2017) report two Chinese BHD patients with novel FLCN mutations. The first case was a 54-year-old man with renal cell carcinoma (RCC), spontaneous pneumothorax (and spontaneous pneumothorax in his family history) and no apparent skin lesions. Genetic testing revealed a novel frameshift mutation (c.946-947delAG) of the FLCN gene. The second case was very similar, a 37-year-old man with chromophobe RCC, no cutaneous lesions, history of spontaneous pneumothorax and family history of pneumothorax. Genetic testing revealed the novel mutation c.770-772delCCT.

Hao et al. (2017) report the case of a 56-year-old Chinese woman who presented with multiple skin papules, pneumothorax and multiple bilateral pulmonary cysts. The patient underwent a tube thoracostomy and had a family history of spontaneous pneumothorax, of pulmonary bullae and of renal cell carcinoma (RCC). The patient’s pneumothorax recurred after 12 years and then she developed another pneumothorax at age 50 years. The patient then underwent surgical intervention. A chest computed tomography (CT) scan showed multiple cystic lesions. Ultrasound examination showed that the patient did not develop RCC, but multiple thyroid nodules were spotted (read previous blog about BHD and thyroid conditions). Genetic testing identified four FLCN mutations. An unreported mutation (c.2297 T > C) in exon 14, and three other mutations that were previously reported to have a minimal correlation to the onset of BHD (Cho et al., 2008) – a mutation in exon 1 (c.-299C > T), a mutation in intron 8 (c.871 + 36G > A) and a mutation in intron 9 (c.1062 + 6C > T).

To date, around 90% of the reported BHD patients are from Europe and the United States. The incidence of skin symptoms seems to be lower among Asian BHD patients (~30%) compared with the higher incidence reported among patients from western countries (~90%) (Murakami et al., 2014; Toro et al., 2008; Furuya et al., 2013). On the other hand, recurrent pneumothorax is observed in approximately 90% of Asian patients compared to the lower percentage among Western countries patients (Kunogi et al., 2010).

In patients with RCC and pulmonary cysts but without cutaneous lesions, screening for mutations in the FLCN gene should be performed, especially for those with a family history of RCC or pneumothorax. Novel FLCN mutations are still being identified all over the world, to add to those already listed in LOVD-hosted FLCN mutation database. Further studies using large cohorts are still needed to clarify possible genotype–phenotype correlations in BHD syndrome.